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Testosterone Insufficiency and Treatment in Women: International Expert Consensus Resolutions
Testosterone Insufficiency
and Treatment in Women:
International Expert
Consensus Resolutions
Gary Donovitz, MD (Chairman), Erika Schwartz, MD, Charles Miller, MD Mickey Barber, MD, Florence Comite, MD, Ken
Janson, MD, Jeffrey Leake, MD, Edwin Lee, MD, Jeffry Life, MD, Luis Martinez, MD, Douglas Woodford, MD
While it is general knowledge that testosterone is used to improve sexual function in women, its non-sexual effects in women
require more in depth review and acknowledgement. To provide a broader scope for this discussion an expert consensus
conference addressing Testosterone insufficiency (TI) in women was held in Orlando, Florida, USA on April 24, 2017.
Participants representing a wide range of specialties were invited on the basis of their clinical and/or research expertise with
the usage of Testosterone therapy and diagnosis and treatment of Testosterone insufficiency (TI) in women
The goal is a review that provides reasonable and prudent rationale for the consideration of testosterone as part of a woman’s
disease prevention and hormone optimization program based on the present scientific and clinical evidence.
Historical Background estrogen, testosterone and placebo in 1985 with 115 pre-menopausal
women post hysterectomy and oophorectomy. Testosterone treated group
Clinical use of testosterone dates to 1939 but became popularized by
showed superior energy improvement, wellbeing, decrease in somatic
Greenblatt in 19491. Since then, testosterone therapy for women became
complaints and psychological symptoms.
a routine component of HRT in Europe and Australia but still limited in the
United States.
Despite the plethora of data in support of the extensive benefits of Terminology
testosterone supplementation in women, the lack of an F.D.A. approved
Optimization of an individual’s testosterone balance and replaces
testosterone product for women, has left medical education in the dark. In
“Testosterone replacement therapy”. “Testosterone insufficiency (TI)”
the most recent, Shifren and Davis2, review of androgens in postmenopausal
replaces “low T” consistent with Morgentaler Consensus recommendations
women the importance of testosterone therapy in premenopausal women
in men.
remains limited primarily to sexual dysfunction.
Our Consensus panel with more than 100,000 patient YEARS experience
with testosterone supplementation in women is excited to share the studies Participants
we reviewed and our clinical and evidence based recommendations.
The panel consisted of ten international specialists in obstetrics and
The format of the consensus group followed Morgentaler et al.3 on gynecology, endocrinology, internal medicine, age management medicine,
testosterone deficiency and treatment in men. and urology. Participants were invited on the basis of established clinical
experience with women’s health, TI and treatment. The choice of multiple
The goal of our review is to raise awareness, open discussion and focus
specialties and geographic diversity was intentional contributing diverse
researchers and clinicians on the broader scope for the use of testosterone
opinions and minimizing regional and specialty-based biases. All experts
and its effects on multiple organ systems.
volunteered their time.
As a consequence of the Women’s Health Initiative (WHI) a 79% decline
in utilization of hormone therapy occured.4 The WHI study didn’t
consider differences in action and risk associated with various forms and
routes of administration of hormones, the age of the participants or pre-
existing conditions and omitted testosterone as a component of hormone
optimization. In contrast Sherwin5 conducted a randomized trial comparing
Page 1 of 1Testosterone Insufficiency and Treatment in Women: International Expert Consensus Resolutions
Methods values for the “mean.” However “normal” values do not always apply to the
individual woman thus leaving reference levels unreliable. Seeking rigid
Two months before the conference each participant was assigned one
guidelines for optimal T levels is also counter to the accepted concept that
statement developed by a working group and asked to provide, 3 to 5 Pub
hormone optimization is not a “one size fits all” treatment (NAMS position
Med, Medline, Cochrane review references pro and con to the statement. At
statement 2013). Thus, TI is a clinical syndrome defined solely by clinical
the conference each participant presented his/her statement, interpretation
symptoms and its successful treatment measured solely by symptomatic
and references. Collaborative discussion and debate led to the resolutions
improvement.
being unanimously agreed upon by the participants.
Carruthers et al.13 also noted poor correlation between symptoms and serum
This review summarizes the resolutions followed by abstracts and supporting
levels of androgens. Kelleher and Handelsman14 noted considerable variation
evidence.
among individuals in the serum levels of testosterone when deficiency
RESOLUTION 1. Testosterone is Not a Male-Exclusive Hormone. It is the symptoms exist.
Most Abundant Gonadal Hormone Throughout a Woman’s Life.
Glaser15 noted “higher doses of testosterone correlated with greater
Although testosterone is known as the “male” hormone, in 2002 improvement in symptoms” in 300 pre and post menopausal women studied.
Dimitrakakis, et al.6 stated testosterone (T) is the most abundant biologically No laboratory correlation was found.
active gonadal hormone throughout the female lifespan. According to Panay
Kratzik16 reported neither the total AMS (Aging Male Score) nor the MRS
and Fenton7 young women’s ovaries produce approximately three- to four-
(Menopause Rating Scale) score correlated with total testosterone serum
times more testosterone than estrogen daily. Measured ranges of androgen
levels.
precursors are similar in women and men.
Most testosterone in the blood is bound to sex hormone–binding globulin
Burger8 noted that quantitatively, women produce more androgen than
(SHBG). Circulating levels of SHBG are affected by genetics, aging, HRT and
estrogen. Only T and DHT bind to the androgen receptor. Other androgens;
other factors17.
DHEA, DHEA-S and Androstenedione are essentially pro-androgens.
Genetic variations in the androgen receptor (AR) gene were noted by
In charting average estradiol (E2) and testosterone levels across the female
Westberg.18 The cysteine, adenine, guanine (CAG) terminal domain of
lifespan, T consistently exceeds E2, usually by 250-300 pg/ml, and between
the AR gene varies in both sexes. Longer chains represent less active
ages 24-30 T levels are 400 pg/ml higher than E2. Both women and men
receptors and lower levels of serum androgens. Serum levels of androgens in
have functional estrogen receptors (ERs) and functional androgen receptors
premenopausal women are influenced by variants in the AR gene. There is
(ARs), with the AR gene located on the X chromosome.9
no “normal” testosterone level in women.
Although T is the major substrate for E2, in proper balance with E2 it is
Due to the difficulty in establishing clear laboratory criteria for a deficiency
equally important for health in both sexes. Testosterone was reported to
syndrome, the consensus proposes the term “Female Testosterone
effectively treat symptoms of menopause as early as 193710. Oddly estrogen
Insufficiency” to represent symptom driven clinical syndrome.
is the hormone of choice for “replacement therapy” in women despite lack
of clear evidence to that fact. RESOLUTION 3. Female Testosterone Insufficiency is a Clinical Syndrome
that May Occur During Any Decade of Adult Life.
RESOLUTION 2. Serum Testosterone Levels do not correlate with
Symptoms of Testosterone deficiency in women. Optimal ranges of Serum Guay et al.19 demonstrated a precipitous age-related decline in all androgens
Testosterone levels in women have not been established. (total T, free T, DHEA-S and Free Androgen Index) in premenopausal women
without sexual dysfunction age 20 to 49 years old.
Established reference ranges for total testosterone, free testosterone
and pre-androgens, below which a woman might be considered androgen In a subsequent study, Guay20 found that premenopausal women with
“deficient” were not found in the literature. Biochemical definition of a complaints of sexual dysfunction had lower adrenal androgen precursors
“female androgen deficiency syndrome” is also lacking in the literature and testosterone than age-matched controls. No differences were noted in
reviewed. Normal ranges posted by various labs reflect averages for a given the ovarian androgen precursors between groups.
population and do not correlate with clinical picture.
Turna et al.21 demonstrated that low total testosterone, free testosterone
In 2002, an expert panel published the Princeton consensus guideline on
11 and DHEA-S levels correlated positively with full-scale FSFI score and FSFI-
Female Androgen Deficiency. The recommended definition of androgen desire, FSFI-arousal, FSFI-lubrication and FSFI-orgasm scores. Slemenda et
deficiency included: [1] a diminished sense of well-being or dysphoric mood; al.22 found hip bone loss associated with lower androgen concentrations in
[2] persistent, unexplained fatigue; lethargy and [3] sexual function changes, premenopausal women.
including decreased libido, sexual receptivity, and pleasure. No biochemical
Zumoff et al.23 noted declining testosterone levels in premenopausal women.
marker diagnosing androgen deficiency was established.
By age 40 a woman has half the mean plasma testosterone levels of a
In discussing androgen production in women, Burger noted that although 21-year-old.
women produce 200-300 micrograms testosterone per day, serum levels
Androgen insufficiency (AI) may explain why despite taking standard
follow circadian, diurnal and menstrual cyclical variation making it difficult to
estrogen/progestin hormone replacement therapy, 67% of women with
define normal ranges. Other variations occur due to stress, sleep, exercise,
premature ovarian failure have diminished bone density associated with
insulin levels and more. According to Davison12 there is a wide range of
increased hip fracture risk as discussed by Kalantaridou and Calis.24
normal. Traditional medicine requires clinical practice to follow “normal”
Page 2 of 8Testosterone Insufficiency and Treatment in Women: International Expert Consensus Resolutions
Pathophysiological states affecting ovarian and/or adrenal function may Maclaran and Panay42 state testosterone has wide-ranging effects via
result in androgen insufficiency in premenopausal women. Young women androgen receptors, found throughout the body, including brain, skin,
with hypothalamic amenorrhea, premature ovarian failure, oophorectomy, adipose tissue, vascular system and bone. Exogenous testosterone positively
premenstrual syndrome, acquired immunodeficiency wasting syndrome, affects bone density, body composition, energy levels and psychological
adrenal insufficiency, hypopituitarism and on certain medications (oral well-being.
estrogen, oral contraceptives and corticosteroids) may have testosterone
Laumann et al.43 evaluated over 1700 women and estimated sexual
deficiency. Additionally, testosterone insufficiency (TI) in young women
dysfunction at 43%. It is biologically plausible that androgen insufficiency
may be under diagnosed because the symptoms are generally nonspecific,
may play a role in a portion of these women. The percentage of these women
awareness of TI is low and the measurement of plasma total and free
complaining of low libido was substantial and varied little between 27-32%
testosterone, not helpful.
at various decades.
RESOLUTION 4. Testosterone Therapy May be Breast Protective.
Basson et al.44 “It remains possible that testosterone deficit hinders
Studies have shown that testosterone may protect the breast from cancer. desire and response but that its systemic production is of little relevance.
Hofling et al.25 showed that addition of Testosterone to a standard estrogen/ Testosterone is produced de novo within the central nervous system starting
progestogen regimen may modulate the stimulatory effects of the estrogen/ from cholesterol. This production appears to be quite widespread within the
progestogen on breast cell proliferation. central nervous system.” The molecular structure of the androgen receptor
in women with and without sexual disorders has not been studied. “Not
As early as 1937,26 it was recognized that breast cancer was an estrogen
only would relative resistance of the androgen receptor theoretically impair
sensitive cancer; testosterone was ‘antagonistic’ to estrogen and was
testosterone activity and contribute to sexual dysfunction, but this could be
used to treat breast cancer as well as other estrogen sensitive diseases
accompanied by relatively high serum testosterone levels due to lessening
including breast pain, chronic mastitis, endometriosis, uterine fibroids and
of the hypothalamic pituitary ovarian axis negative feedback.” Goldblatt et
dysfunctional uterine bleeding.
al.45 conducted a randomized, placebo controlled crossover efficacy study
Dimitrakakis and Glaser27 stated “testosterone and DHEA-s levels in saliva using testosterone crème (10 mg/day) in premenopausal females with low
were statistically significantly lower in breast cancer patients compared to libido and serum testosterone levels in the lower third of the reproductive
controls and more profound in post-menopausal women with breast cancer.” range. It included women on oral contraceptives aged 30 to 45 years with
total testosterone levels less than 2.2 nmol/l. (62.8 ng/dl). The treatment
Clinical trials in primates and humans28 have confirmed that testosterone has
group showed improvement in wellbeing, mood and sexual function and a
a beneficial effect on breast tissue by decreasing breast cell proliferation and
corresponding increase in serum testosterone and FAI.
preventing stimulation by E2.
Davis et al.46 showed that a daily 90ul dose of transdermal testosterone in
Although testosterone is breast protective, it can aromatize to E2 and have a
sexually active women age 35 to 45 years with low libido and low circulating
secondary, stimulatory effect via estrogen receptor (ER) alpha.29
testosterone improved sexual satisfaction scores.
Friedman,30 reports that testosterone down regulates the Estrogen alpha
OCs reduce the level of free testosterone in a woman’s body by suppressing
receptor and may inhibit the proliferative effect of estrogen through this
the production of testosterone in the ovaries and adrenals. OCs increase
process.
SHBG (sex hormone-binding globulin) levels, inhibiting the conversion of free
Starting in the 1940s, androgen therapy was used to induce regression testosterone to dihydrotestosterone (DHT). Due to increase in SHBG levels,
of breast cancer metastasis with promising results. Over time the use of free T levels decrease twice as much as total Testosterone47 according to a
androgen-based hormonal therapies were largely abandoned primarily meta-analysis of the effect of combined OC on T levels in healthy women.
due to testosterone’s masculinizing side- effects in some women albeit
Glaser et al.48 demonstrated beneficial effects of testosterone therapy on
decreasing the dose or discontinuing use eliminated the side-effects.31-39
somatic, psychological, and urologic complaints in both pre- and post-
More recently, studies using exogenous Testosterone have shown that menopausal women. The validated Menopause Rating Scale (MRS) showed
Testosterone in combination with estrogen may reduce, the risk of breast significant improvement in all 11 symptoms on the screening questionnaire
cancer. Dimitrakakis et al.40 followed 508 postmenopausal women receiving during treatment period.
testosterone in addition to customary HRT in South Australia and found the
RESOLUTION 6. Testosterone Insufficiency May Be Associated with an
addition of Testosterone reduced breast cancer incidence—to numbers lower
Increased Risk of CVD in Women.
than those observed in the general population who never took hormones.
Testosterone insufficiency may increase cardiovascular risk in women.
Glaser et al.41 in the Dayton Study reported 8-year data using both
In 2007, Debing et al.49 reported on a study of endogenous sex hormone
testosterone and testosterone with anastrozole pellets finding a marked
levels in postmenopausal women undergoing carotid artery endarterectomy.
reduction in the incidence of breast cancer 76/100,000 women years in
Significant association between low serum androgen levels and severe ICA
comparison to an age matched S.E.E.R. incidence rate of 297/100,000
atherosclerosis in postmenopausal women were found. Findings suggest
women years.
that higher, yet physiologic levels of androgens in postmenopausal women
RESOLUTION 5. Testosterone Insufficiency in Women Negatively Affect may have a protective role against the development of atherosclerosis of
Sexuality, General Health and Quality of Life. Testosterone Supplementation ICA.
May Positively Influence Sexuality, General Health and Quality of Life.
In their review of the literature, Glaser and Dimitrakakis50 found substantial
Page 3 of 8Testosterone Insufficiency and Treatment in Women: International Expert Consensus Resolutions
evidence that testosterone is cardio protective and adequate levels decrease than the placebo group.
the risk of cardiovascular disease. Unlike anabolic and oral, synthetic steroids,
A pilot study64 of healthy post menopausal women receiving testosterone
there is no evidence that human identical testosterone supplementation has
spray and controls for 26 weeks showed pTestosterone Insufficiency and Treatment in Women: International Expert Consensus Resolutions
were observed in women treated with testosterone. Total cholesterol and with sub-cutaneous testosterone implants experienced successful relief in
LDL decreased in both groups, while total body fat-free mass increased in vasomotor, insomnia, fatigue symptoms, decreased libido, and cognitive
the testosterone group only. decline.
Elizabeth Barrett-Connor76 followed premenopausal women through the Cameron and Braunstein concluded in 200488 that “symptoms of androgen
menopausal transition, reviewed CHD risk factors and outcomes based on insufficiency in women may include a diminished sense of well-being, low
and prospective cohort studies of younger and older women with CHD risk mood, fatigue, and hypoactive sexual desire disorder with decreased libido,
markers or disease outcomes in the context of menopausal history. Those or decreased sexual receptivity and pleasure that cause a great deal of
studies suggest that oophorectomized women are at greater risk for CHD personal distress. The evidence from clinical trials supports the correlation
than intact women. These findings demonstrated increasing importance of between decreased endogenous androgen levels and the presence of these
low testosterone and the harmful effect of oophorectomy on cardiovascular symptoms and their alleviation with the administration of Testosterone.
risk.
There are no Food and Drug Administration- approved androgen
In a 3-year study of 61 oophorectomized patients treated with estradiol preparations on the market for treating androgen insufficiency in women.
pellets or estradiol plus testosterone, lipoprotein levels associated with each There are however multiple sources for human identical testosterone.
of the two treatment regimens were compared. Levels were also measured Compounding pharmacies were the original source but problems with
in 67 untreated age-matched bilaterally oophorectomized women. LDL consistent purity, potency, and sterility called their products into question.
cholesterol in the estrogen/testosterone treated group were lower than in Treatment with exogenous testosterone from 503b FDA approved and
the untreated group.77 supervised outsourced pharmacies conforms to the highest level of safety
and sterility standards in the industry today.
In a study of 8,412 women—2,103 testosterone users and 6,309 controls—van
Staa and Sprafka78 found no significant increase in the risk of cardiovascular In 2012, Maclaran and Panay89 reviewed the data on postmenopausal
disease or breast cancer in women using testosterone (implants, tablets, or testosterone therapy, focusing specifically on the effects of testosterone on
injections), There were no statistically significant differences between the breast, endometrium and cardiovascular health. They found testosterone
cohorts in the rates of cerebrovascular disease, ischemic heart disease, safe and recommended more pre and postmenopausal research be
breast cancer, deep vein thrombosis/pulmonary embolism, diabetes mellitus conducted to further demonstrate cardiovascular and breast safety and
or acute hepatitis. possibly influence regulatory agencies to give better consideration to the
broader use of testosterone in women.
S. Worboys et al.79 investigated the effects of testosterone implant
therapy on arterial reactivity encompassing endothelial-dependent and
-independent vasodilation in women using hormone replacement therapy
Discussion
(HRT). Results showed parenteral testosterone therapy improved both
endothelial-dependent (flow-mediated) and endothelium-independent In the face of considerable public and scientific confusion regarding
(GTN-mediated) brachial artery vasodilation in postmenopausal women on testosterone insufficiency and its treatment in women, an expert consensus
long-term estrogen therapy. conference was held to define fundamental tenets based on the best available
evidence and to provide an accurate scientific framework for practitioners to
An in vivo study of human umbilical vein endothelial cells placed into mice
identify and treat testosterone insufficiency as it may present in the female
found that “estradiol and testosterone have a synergistic effect on early
patient. These resolutions address key areas representing areas of concern
stage atherosclerosis” and they suppress development of atherosclerosis by
with the goal of removing barriers to improving quality of life and care in
reducing lipid lesions, formation of foam cells, endothelial injury, modulating
women’s health in wellness.
the coagulation system function and inhibiting inflammation.80
This review presents a broader use for testosterone in women. The timing is
K. Maclaran and N. Panay81 found no association between testosterone
critical to women’s health. In 2002, post WHI, 79% of women discontinued
and increased risk of cardiovascular events. Current data indicate that
usage of HRT. The impact on quality of life alone was a set-back for post-
testosterone supplementation isn’t associated with cardiovascular, breast or
menopausal women everywhere. Fifteen years of insecurity and indecision
endometrial side-effects.
about the safety of HRT followed. In September 12, 2017 an article in
RESOLUTION 10. Studies of Testosterone supplementation show benefits J.A.M.A. by the principal investigators of WHI reported that all the women
exceed the risk and Consistent Purity and Potency can be Achieved followed in the WHI study for 18 years were found to have similar all-cause
mortality, cardiovascular mortality, and cancer mortality whether they were
The use of testosterone in women dates back to 1939 becoming popularized
in the treatment group or not.90 The impact of this report is far reaching
in hysterectomized women as per Greenblatt et al.82 The use of testosterone
and brings new perspective on HRT in general. Endorsement by the medical
pellets antedated use of transdermal preparations. Sub-cutaneous
societies is necessary to change HRT prescribing habits and testosterone
testosterone pellet therapy has been used on five continents for nearly 80
treatment is unfortunately not even in the conversation.
years.
Many professionals in multiple primary care specialties have been hesitant to
Jockenhovel et al.83 and Kelleher et al.84 published pharmacokinetic studies
recommend testosterone to female patients because of the lack of an FDA
on sub-cutaneous testosterone pellet absorption which was predictable
approved product. The Consensus group presented a plethora of data and
enough to allow calculation of proper dosing in men and women.
studies that cannot be ignored when the health and wellbeing of women
Cardoza et al.85 in 1984, reported 60% of women with TI in the study treated are at stake. The FDA is responsible for determining pharmacotherapeutics
Page 5 of 8Testosterone Insufficiency and Treatment in Women: International Expert Consensus Resolutions
of new medications. They are not tasked to tell practitioners how to References
practice medicine. The use of human identical testosterone in women to
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